AUTHOR=Baban Anwar , Cicenia Marianna , Magliozzi Monia , Parlapiano Giovanni , Cirillo Marco , Pascolini Giulia , Fattori Fabiana , Gnazzo Maria , Bruno Pasqualina , De Luca Lorenzo , Di Chiara Luca , Francalanci Paola , Udd Bjarne , Secinaro Aurelio , Amodeo Antonio , Bertini Enrico Silvio , Savarese Marco , Drago Fabrizio , Novelli Antonio 

TITLE=Biallelic truncating variants in children with titinopathy represent a recognizable condition with distinctive muscular and cardiac characteristics: a report on five patients

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1210378

DOI=10.3389/fcvm.2023.1210378

ISSN=2297-055X

ABSTRACT=<sec><title>Background</title><p>Monoallelic and biallelic <italic>TTN</italic> truncating variants (<italic>TTNtv</italic>) may be responsible for a wide spectrum of musculoskeletal and cardiac disorders with different age at onset. Although the prevalence of heterozygous <italic>TTNtv</italic> is relatively high in the general population, cardiac phenotyping (mainly cardiomyopathies, CMPs) in biallelic titinopathy has rarely been described in children.</p></sec><sec><title>Methods</title><p>We reviewed the medical records of pediatric patients with biallelic <italic>TTNtv</italic> and cardiac involvement. Clinical exome sequencing excluded pathogenic/likely pathogenic variants in major CMP genes.</p></sec><sec><title>Results</title><p>Five pediatric patients (four male) with biallelic <italic>TTNtv</italic> were included. Major arthrogryposis multiplex was observed in four patients; no patient showed intellectual disability. At a cardiac level, congenital heart defects (atrial and ventricular septal defects, <italic>n</italic> = 3) and left ventricular non-compaction (<italic>n</italic> = 1) were reported. All patients had dilated cardiomyopathy (DCM) diagnosed at birth in one patient and at the age of 10, 13, 14, and 17 years in the other four patients. Heart rhythm monitoring showed tachyarrhythmias (premature ventricular contractions, <italic>n</italic> = 2; non-sustained ventricular tachycardia, <italic>n</italic> = 2) and nocturnal first-degree atrio-ventricular block (<italic>n</italic> = 2). Cardiac magnetic resonance (CMR) imaging was performed in all patients and revealed a peculiar late gadolinium enhancement distribution in three patients. HyperCKemia was present in two patients and end-stage heart failure in four. End-organ damage requiring heart transplantation (HT) was indicated in two patients, who were operated on successfully.</p></sec><sec><title>Conclusion</title><p>Biallelic <italic>TTNtv</italic> should be considered when evaluating children with severe and early-onset DCM, particularly if skeletal and muscular abnormalities are present, e.g., arthrogryposis multiplex and congenital progressive myopathy. End-stage heart failure is common and may require HT.</p></sec>